Synthesis of 3-[beta-keto-gamma-(2-piperidyl) propyl]-4-quinazolone compounds



- l atente cl 51511.1 ill UNITED STATES sYNTnE sIsor Is PIPERIDYL)COMPOUNDS A ENT OFF E-3J2 -[BETA-KETO-GAMMA-(2- PROPYL] 4 QUINAZOLONE gBernard. R. Baker, Nanuet, N. Y., and Merle V.

Querr-y,- Westwood, N.

Cyanamid Company, ration of Maine J as'signors to American New York, N.Y., a corpo- No Drawing. Applicationt-Ma rch 17, 1951, SerialNo.-216,261

This invention relates to a ilw' m paring compounds havingantimalarialactivity,

and more particularly'to compounds represented by the formula:

limits and may be on one or more of the two, five, six, seven or eightpositions of the quinazo- Substituents of the following types i lonenucleus. are of value: halogen, for instance 'Cl, Br, and 7 Fl; alkoxyand aryloxy, for instance OCH3, OC2H5, -OCH2C6H5, and OCsH; hydroxylradicals; lower alkyl radicals, for instance methyl,

ethyl, propyl and butyl; aryl radicals, for instance phenyl andsubstituted phenyl radicals; acyl radicals, for instance COR in whichRis hydrogen or lower alkyl; acyloxy radicals, for instance OCOR in whichB. may represent-H or lower alkyl; carboxyl radicals (-COOl-I) and theesters, amides and salts thereof.

The radical represented by R in. the above formula may also vary withinwide limits as long as it is attached to the piperidine nucleus by anoxygen to carbon linkage. By wayof illustration, suitable substituentsare: hydro'xy; aryloxy, for instance, henoxy; alkoxy, for instancemethoxy, ethoxy and propoxy; .aralkoxy, for instance, 'alphatcloxy;acyloxy, for instance .acetoxy and benzoloxy; and the like. Suchsubstituent's may be on one or more of the three, four,"five and sixpositions of the piperidine nucleus.

-While compounds of the above formula can be prepared in numerous waysit has been found that they may conveniently be prepared under certainconditionsby the catalytic reduction of the corre- 10 Claims. (01. 260-256.4)

med-apes;

" sponding tetrahydropyridyl compounds in accordance with the followingequation:

V 5 2 H2 I cat N-OHr-C-CH an H s) R in which R and R are as defined.above. Tetrae hydropyridyl compounds of the formula 2) above constitutethe subject matter of .a co-pending U. S. application S. N. 216,262 byB. R. Baker filed concurrently herewith. I Ifone attempts, tohydrogenate a compound represented by the formula (2) above under ordi-'nary conditions it will be found that the quinazol'one nucleusand/orthe carbonylgroup are to a arge extent.reduce'dj bjefore theduction oftheetrahydropyridylnucleus is accomplished. This not onlyresults in an lexcessiyewas'te of starting nc Z mduaS which is next toimpossible jo 5g J'aratej. By the method of this in ventiom -howevery itis possible to hydrogenate the ,tet'rahy- .dropyridyl nucleus ofcompounds represented by thefo'rmula (2) above without unduejreductionof v thejquinazolone nucleus or the carbonylgroup The process of thisinvention comprises hyd genating the 3-[beta keto-ganirha-(tetrahydZ-pyridyl) propyl] -'4-quinazolone compound i a stronglyacidic medium.The product maythenbeobtainedfrom the reaction mixture as the acidadditionfsalt of the acid employed to acidify the reaction mixture orthe reaction mixture may be neutralized and the product obtained as thefree base. '4 The reasons for the selective reduction of. thetetrahydropyridyl group under acidic conditions are not fully understoodbut are believed to be due to the presence or absence of resonance inthe quinazolone and tetrahydropyridyl nuclei. As is 50 well known bythose skilled in "the art, unsaturat- "materials but also results inamix'ture o f reduc.5 H

ed compounds displaying the phenomenon of resonance usually show greatlyincreased stability over corresponding compounds in which resonance isnot present. This may be illustrated by, for instance the benzene ringwhich is much more diiiicult to hydrogenate than, for instancecyclohexene. If then the quinazolone nucleus and the tetrahydropyridylnucleus of 3-[beta-keto-gamma (tetrahydro 2 pyridyl) propyll-4-quinazolones were both resonant groups, it might be expected that onewould experience difiiculty in reducing one group without at the sametime reducing the other or in reducing either without also reducing thecarbonyl group. Further, if the resonance in one of these groups couldbe destroyed without destroying the resonance in the other, it might bepossible to selectively reduce the one group without undue reduction ofother portions of the molecule.

While there would appear to be no resonance in compounds of the formulawhere R is alkyl, as such compounds are readily reduced in neutralsolution with a variety of catalyst, it is believed that theintroduction of a carbonyl group in the beta position of theside chaindoes result in resonance, at least in neutral solution. This isindicated by the presence of strong peaks at about 310m in the ultraviolet absorption spectrum of compounds of the formula v (2) above whichpeaks cannot be explainedbyth other portions of the molecule. If thenthis resonance of the tetrahydropyridyl group is, in some unexplainedmanner, destroyed by a highly acidic medium without in turn destroyingthe resonance of the quinazolone nucleus, it might be theoreti callypossible to selectively reduce the former without undue reduction oi thecarbonyl group or the quinazolone nucleus. While this would appear to bethe most logical reason for the success of the new process, it is notintended that this invention be limited by chemical theory and theinvention is to be construed as covering these new reactions regardlessof the mode of their operation. 7

The new reaction is preferably performed in aqueous solution. Thereaction may also be performed in various organic solvents asillustrated by the following: aliphatic alcohols, for instance ethylalcohol; cyclic ethers, for instance dioxane; glycol ethers, forinstance 2-methoxyethanol; and lower fatty acids, for instance aceticacid. The solution may be made acidic with almost any nonoxidizingmineral acid, for instance hydrochloric, hydrobromic, sulphuric andphosphoric, or the solution maybe made acidic with certain organicacids, for instance toluene sulfonic. It is important, however, that theacid have a dissociation constant in water at 25 C. of at least aboutIXIO- as the selectivity of the reaction decreases rapidly with weakeracids. The concentration of the acid may vary within wide limits but theacid should bepresent in a molar quantity at least equal to thetetrahydropyridyl compound and preferably in excess. In fact, thereaction proceeds satisfactorily in acid concentrations of about IN to2lN and acid concentrations of 4N to 8N are preferred.

Suitable catalysts are illustrated by the following: metals of groupVIII of the sixth period, for instance platinum; metals of group VIII ofthe fourth period, for instance palladium. Of course, in some instancesthe metal may be originally present in the form of its oxide, but thisis equivalent to using the free metal as the oxide is reduced to themetal by the hydrogen present in the reaction mixture. The catalyst isefiective in catalytic amounts but an excess is not detrimental.Platinum is the preferred catalyst.

The new reaction may be conducted over a large range of temperatures andpressures. For instance, temperatures ranging from about 0-140 C. andpressures from about atmospheric to 2,000 pounds per square inch or evenhigher are satisfactory. As the reaction goes well at low pressures,pressures of from about 1 to 3 atmospheres are preferred for reasons ofconvenience. The optimum reaction temperature is about 20-35 C.

The reaction time is best measured by the amount of hydrogen absorbed asthe actual time will vary widely depending upon a number of factors, forinstance temperature, pressure and the type and condition of thecatalyst. For example, the complete reaction may take from onehalf tofive hours at 20 C. and from about five minutes to one hour at C.Theoretically, of course, the reaction will be complete when one mole ofhydrogen has been absorbed for each mole of 3 -[beta keto gammatetrahydro 2 pyridyl) propyl] -l-quinazolone originally present in thereaction mixture. Since, however, even under optimum conditions thereduction is not selective, best results will be obtained in a batchprocess if the reaction is continued until agent 1.0 to 1.2 mols ofhydrogenhave been absorbed for each mole of 3-[beta-keto-gamma-(tetrahydro 2 pyridyl) propyll 4 quinazolone originally present in thereaction mixture. Under no circumstances should the reaction becontinued until more than about 1.4 mols of hydrogen per mole oftetrahydropyridyl compound have been absorbed as this results in amixture of reduction products which is extremely difiicult to separate.As the percentage of by-products formed increases as the reactionapproaches completion, the reaction lends itself well to a cyclicprocess. In other words, the reaction may be stopped after about 0.5 molof hydrogen per mol of tetrahydropyridyl compound has been absorbed, thereduction products removed, makeup tetrahydropyridyl compound and acidadded and the reduction continued.

The process will be more particularly described by means of thefollowing illustrative examples in which all parts are by Weight unlessotherwise indicated.

Ezcample I A solution of 6.0 parts by weight of sodium methoxide, 24parts by volume of methyl acetoacetate and 30 parts by weight ofgammabromopropylphthalimide (Ber., 21, 2671) in 1500 parts by volume ofmethanol is refluxed for sixteen hours, then 300 parts by volume of 3Nhydrochloric acid is added and the refluxing continued for four hours.The solution is concentrated in vacuo and the separating oil extractedwith ethyl acetate. Evaporation of the extract gives crude1-phthalimido-5-hexanone as an oil. When purified through its sodiumbisulfite derivative, this compound forms white crystals having amelting point of 66-68 C. It is readily soluble in alcohol, acetone,ether or benzene but insoluble in water or petroleum ether.

A mixture of 49 parts by weight of crude 1-phthalimido-5-hexanone, 490parts by volume of benzene, 29 parts by volume of absolute ethanol, 33.3parts by weight of ethyl 4-quinazolone-3-acetate and 9.8 parts by weightof sodium methoxide is refluxed for one hour, then acidified with 40parts by volume of acetic acid and washed with water. The organicsolution is evaporated, the residue dissolved in ethyl acetate andshaken with 300 parts by volume of cupric acetate. The copper derivativeof 3-(beta,delta-diketoomega-phthalimidooctyl) -4quinazolone separatesas blue green crystals having a melting point of about 235 C. withdecomposition.

A mixture of 1 part by weight of the copper derivative of 3 (beta,deltadiketo omega phthalimidooctyl) -4-quinazolone and parts by volume of 6Nhydrochloric acid is refluxed for six hours. The solution isconcentrated in vacuo until phthalic acid separates, then it is cooledand filtered. The filtrate is evaporated to dryness in vacuo, theresidue dissolved in water and poured into excess ammonia water. Themixture is then extracted with chloroform. The combined extracts areevaporated to dryness in vacuo after clarification with activated carbon(Norit). Trituration of the residue with ethyl acetate gives about .16part by weight of 3-[betaketo gamma (1,4,5,6 tetrahydro 2 pyridyl)propyl] -4-quinazolone. having a melting point of about 177-180 C.Recrystallization from alcohol gives white crystals having a meltingpoint of about 175-178 C. This compound is soluble in hot alcohol, butinsoluble in cold alcohol, benzene, ethyl acetate or petroleum ether. Itis moderately soluble in chloroform.

keto gamma-(l, l,5,6-tetrahydro-2-pyridyl) propyll-4-quinazolone in 50parts by volume of methanol and 0.5 part by volume concentratedhydrochloric acid is shaken with hydrogen at 1 atmosphere in thepresence of .1 part by weight of platinum oxide catalyst until onemol-equivalent of hydrogen is absorbed. Evaporation of the filteredsolution to dryness in vacuo and trituration with absolute alcohol giveswhite crystals of 3-[beta-keto-delta-(2 piperidyDpropyl] 4 quinazolonedihydrochloride monohydrate having a melting point of about 212-214= C.with decomposition. This compound is soluble in water or hot methanol,but insoluble in ethanol, acetone, ether or benzene.

Example II A solution of 174 parts by weight of allylphthalimide (Ben,23, 999) and 285 parts by weight of mercuric acetate in 1745 parts byvolume of methanol is refluxed with stirring for ten minutes. A solutionof 156 parts by weight of potassium iodide in 310 parts by volume ofwater is added and the mixture again refluxed ten minutes. Then 256parts by weight of iodine is added. After being refluxed for fifteenminutes more a solution of 178 parts by weight of potassium iodide in1260 parts by volume of water is added followed by suflicient sodiumbisulfite to bleach the excess iodine. The mixture is diluted to 5000parts by volume with water and cooled. The precipitate is recrystallizedfrom alcohol giving white crystals of 2-methoxy-3-iodo-propylphthalimide having a melting point of about 105-107 C.

A mixture of 4'7 parts by weight of sodium methoxide, 464 parts byvolume of t-butyl alcohol, 243 parts by weight ofZ-methoxy-S-iodopropylphthalimide and 165 parts by volume of'methyl 35ves by extraction with benzene A solution of .72 part by weight of aw e6. acetoacet'ate is refluxed forty-two hours, then acidified with 47parts by volume of acetic acid and evaporated to dryness in vacuo. Theresidue, is refluxed with 555 parts by volume of alcohol and 555 partsby volume of 3N hydrochloric acid for three hours, concentrated to aboutone-half volume in vacuo, diluted with water and extracted with ethylacetate. The extract, washed with aqueous sodium bicarbonate and dried,is evaporated to dryness. The residual crude 1-phthalimido-2-methoxy-5-hexanone is about 36% pure. It is purifiedthrough its solid sodium bisulfite derivative With about 99% recovery.This ketone is an oil soluble in alcohol, ethyl acetate and benzene, butinsoluble in water. Its 2,4 dinitrophenylhydrazone forms orange crystalshaving a melting point of about 180.5- 181 C.

A mixture of 41 parts by weight of l-phthalimido-2-methoxy-5-hexanoneand 410 parts by volume of 6N hydrochloric acid is refluxed three hours,cooled, filtered and the filtrate evaporated to dryness in vacuo. Theresidual crude 1- amino-2-methoxy-5-hexanone hydrochloride is dissolvedin 176 parts by volume of water and basified with a solution of 12.6parts by weight of sodium hydroxide in 74 parts by volume of water.After the addition of 17.9 parts by volume of benzoyl chloride, themixture is stirred'twenty minutes. The mixture is treated with 6.3 partsby weight of sodium hydroxide in 22 parts by volume of water, then 4.5parts by volume of benzoyl chloride is added and the stirring continuedfor thirty minutes more. The oil is re- The combined extracts, washedwith dilute acid and water, are evaporated leaving 26 parts by weight of1-benzamido-2-methoxy-5-hexanone as an oil soluble in alcohol, benzeneor acetone, but insoluble in Water. The 2,4-dinitrophenylhydrazone formsyellow crystals having a melting point of about 132-134 C.

A mixture of 26 parts by weight of l-benza mido 2 methoxy 5 hexanone,28.5 parts by weight of ethyl 4-duanazolone-3-acetate, 260 parts byvolume of benzene, 22 parts by volume of absolute alcohol and 7.6 partsby weight of sodium methoxide is refluxed for one hour, acidified with15 parts by volume of acetic acid and washed with water. The organiclayer is evaporated, the residue dissolved in 236 parts by volume ofethyl acetate and treated with 213 parts by volume of 10% cupricacetate. The blue crystals of the cooper derivative of 3-(2,4-diketo-7-methoxy-S-benzamidooctyl) -4-quinazolone separate; melting point about21a-22o C. with decomposition. This compound is insoluble in commonorganic solvents.

A solution of 122 parts by weight of the copper derivative of3-(2,4-diketo-7-methoxy-8-benzamidooctyl) -4-quinazolone in 47 parts byvolume of water and 15.6 parts by volume of 96% sulfuric acid isrefluxed for two hours, then poured into ice and 62 parts by volume of28% ammonia water. The mixture is extracted with chloroform. The driedextracts are evaporated and the residue refluxed with 51 parts by volumeof 48% hydrobromic acid for twenty minutes, then poured into ice and 51parts by volume of 28% ammonia water. The precipitate is collected on afilter and washed with water. The combined filtrate and washings areextracted with chloroform. The precipitate is added to the extractsheated and suflicient 2-methoxyethanol added to dis solve the solid. Thesolution is dried and evapo-' rated in vacuo. 'Tritu'ration of theresidue with ethyl acetate gives about 4 parts by weight of3-[beta-keto-gamma-(5-hydroxy 1,456 tetrahydro-Z-pyridyl) propyll-4-quinazolone having a melting point of about 219-223" C.Recrystallization from alcohol gives white needles having a meltingpoint of about 229-23G C. This compound is soluble in hot alcohol or hotZ-methoxyethanol but insoluble in cold alcohol, benzene or petroleumether.

A solution of 1.6 part by weight of 3-[betaketo gamma(-hydroxy-1,4,5,6-tetrahydro-2- pyridyl) propyll -4-quinazolone in 25parts by volume of 6N hydrochloric acid is shaken with hydrogen at 1atmosphere in the presence of part by weight of platinum oxide until onemolequivalent of hydrogen is absorbed (about two hours). The filteredsolution is evaporated to dryness in vacuo. A solution of the residue inparts by volume of water is basil-led with potassium carbonate andextracted with chloroform. The combined dried extracts are evaporatedand the residue treated with absolute alcoholic hydrogen chloride. Whitecrystals of B-Ebeta-ketogamma (5-hydroxy-2-piperidyl) propyl]-4-quinazolone dihydrochloride having a melting point of about ZZZ-225C. with decomposition, separate. ecrystallization from methanol by theaddition of absolute alcoholic hydrogen chloride raises the meltingpoint to about 225-226 C. with decomposition. This compound is solublein water and hot methanol, but insoluble in ethanol, acetone or ether.

Example III A mixture of 4 parts by weight of acetantfiranil (J. Am.Chem. Soc., 29, 529), 1.85 parts by weight of glycine and 4 parts byvolume of diethyl carbitol is heated at 175-185" C. for fifteen minutes.Addition of parts by volume of alcohol and cooling give white crystalsof 2-methyl-4-quinazolone-3-acetic acid having a melting point of about263 C. with decomposition after recrystallization from Z-methoxyethanol.

To a suspension of 3 parts by weight of 2- methyl-4-quinazolone-3-aceticacid in 17 parts by volume of methanol there is added 1.7 parts byvolume of acetyl chloride. The solution is refluxed for thirty minutes,cooled, diluted with water and neutralized with sodium bicarbonate. Themixture is extracted with chloroform. The extracts are evaporated andthe residue recrystallized from benzene-heptane to give white crystalsofmethyl 2-methyl-4-quinazolone-3-acetate having a melting point ofabout 114-115 C;

A mixture of 11.4 parts by Weight of sodium methoxide, 285 parts byvolume of methanol, 4.5 parts by volume of methylacetoacetate and 57parts by weight of gamma-bromopropylphthalimide is refluxed for eighteenhours, diluted with several volumes of water and extracted withchloroform. The combined extracts, evaporated to dryness in vacuo, leavea residue which is refluxed with 570 parts by volume of 6N hydrochloricacid for nine hours. The cooled mixture is filtered from phthalic acidand the filtrate evaporated to dryness in vacuo. The residue of1-amino-5-hexanone hydrochloride is dissolved in 168 parts by volume ofwater, then a solution of 14 parts by weight of sodium hydroxide in 84parts by volume of water is added. The stirred mixture is treateddropwise with 23 parts by volume of ethyl chlorocarbonate over a periodof ten minutes, then stirred twenty minutes longer. After the additionof 7 parts by weight of sodium hydroxide in 42 parts by volume of waterand 5 parts by volume of ethyl chlorocarbonate, the mixture is stirredten minutes more. The oil is extracted with benzene. Evaporation gives1carbethoxyamino-5-hexanone as an oil which gives a yellow2,4-dinitrophenylhydrazone having a melting point of about 128-129 C.

A mixture of 5.8 parts by weight of methyl 2-methyl-4-quinazolone-{i-acetate, '7 parts by weight of 1-carbethoxyamino-5-hexanone, 83 partsby volume of benzene, 5 parts by volume of absolute alcohol and 1.7parts by weight of sodium methoxide is refluxed for one hour. The bluecrystals of the copper derivative of Z-methyl-3-(2,4-diketo-8-carbethoxyaminooctyl) 4 quinazolone separate; meltingpoint about 201-202 C. with decomposition. This compound is insoluble incommon solvents.

A solution of .15 part by weight of the copper salt of 2-methyl-3-(2,l-diketo-8-carbethoxyaminooctyl) -4-quinazolone in 1.45 parts by volumeof 48% hydrobromic acid is refluxed for five minutes, then poured intoice and 3 parts by volume of 28% ammonia water and extracted withchloroform. The dried extracts are evaporated and the residue trituratedwith ethyl acetate to give 2-methyl-3- [beta-keto-gamma-(1,4,5,6-tetrahydro-2-pyridyl) propyl] -4-quinaz0lone having a meltingpoint of about 195-198 C. Recrystallization from alcohol gives Whiteleaflets having a melting point of about 198-198.5 C. This compound issoluble in hot alcohol or chloroform, but insoluble in cold alcohol,water, ethyl acetate or petroleum ether.

""TA solution of 1.25 parts by weight of Z-methyl-3-[beta-keto-gamma-(1,4,5,6-tetrahydro 2 pyrydyl)propyll-l-quinazolonein 50 parts by vol-' ume of 6N hydrochloric acid is shaken with hydrogenin the presence of .1 part by weight of platinum oxide catalyst untilone moi-equivalent of hydrogen is absorbed (about three hours). Thefiltered solution is evaporated to dryness in vacuo and the residuecrystallized from absolute alcoholic hydrogen chloride by the additionof ether. Recrystallization from absolute alcoholether gives hygroscopicwhite crystals of 2- methyl-3-[beta-keto-gamma (2 piperidyl)propyll-4-quinazolone dihydrochloride monohydrate having a melting pointof about 187-189" C. with decomposition. This compound is soluble inwater, methanol or ethanol, but insoluble in ether, acetone or benzene.

Emample IV To a solution of 44 parts by weight of 5-methyl-4-quinazolone (Ber., 52, 1084) and 14.8 parts by weight of sodiummethoxide in parts by volume of absolute alcohol there is added 28.8parts by volume of ethyl chloroacetate. The mixture is refluxed twohours, diluted with Water and extracted with chloroform. Evaporation ofthe extracts to dryness in vacuo and crystallization of the residue fromheptane gives ethyl 5-methyl- 4-quinazolone-3-acetate.

Example III is repeated except that 30.5 parts by weight of ethyl5-methyl--quinazolone-3- acetate are employed in place of the ethyl 4-quinazolone-tS-acetate of that example. White crystals of 3-[beta-keto-gamma- 5-hydroxy-2- piperidyl) propyl]-5-methyl-4-quinazolone dihydrochloride are obtained in equally goodyield.

Example V A mixture of 48 parts by weight of 6-chloro- 9 anthranilicacid (Monats. 22, 448) in 42 parts by volume of formamide is heated atabout 130-135 C. for forty-five minutes and at 175 C. for seventy-fiveminutes. Addition of 72 parts by volume of 2-methoxyethanol and 720parts by volume of water gives -chl0ro-4-quinazolone having a meltingpoint of about 210 C. after recrystallization from aqueous2-methoxyethanol.

To a solution of 37.2 parts by weight of 5- chloro-4quinazolone and 11.1parts by weight of sodium methoxide in 300 parts by volume of absolutealcohol there is added 21.6 parts by volume of ethyl chloroacetate. Themixture is refluxed two hours, diluted with water and extracted withchloroform. Evaporation of the extracts to dryness in vacuo andcrystallization of the residue from he tane gives ethyl 5-chloro-4-ouinazolone-3-acetate.

Example III is repeated except that 32.5 parts by weight of ethyl5-chloro-4-quinazolone-3- acetate are employed in place of the ethyl 4-quinazolone-B-acetate of that example. White crystals of3-[beta-keto-gamma-(5-hydroxy-2- piperidyl) -propyll-5-chloro-4-quinazolone dihydrochloride are obtained in equally goodyield.

We claim:

1. The method of preparing 3-[beta-ketogamma-(2 niperidyl) -propyl] 4quinazolones and acid addition salts thereof which comprises reacting a3-[beta-keto-gamma-(tetrahydro-2- pyridyl)-propyll-4-quinazolone withnot more than 1.4 moi-equivalents of hydrogen in the presence of ahydrogenation catalyst and in an inert solvent containing at least onemol-equivalent of a nonoxidizing acid having a dissociation-constant inwater of at least 1 X 2. The method of claim 1 wherein said 3[betaketogamma-(tetrahydro-Z-pyridyl) propyll 4- quinazolone is3-[beta-keto-gamma-(1,4,5,6-tet rahydro-Z-pyridyl) propyll-4-quinazolone.

3. The method of preparing3-[beta-keto-gamma-(hydroxy-Z-piperidyl)-propyll 4 quinazolones whichcomprises reacting a 3-[beta-ketogamma-(hydroxy tetrahydro 2 pyridyl)-propyll-4-quinazolone with not more than 1.4 molequivalents of hydrogenin the presence of a hydrogenation catalyst and in an inert solventcontaining at least one mol-equivalent of a non- 10 oxidizing acidhaving a dissociation constant in water of at least 1 10- 4. The methodof preparing 3-[beta-ketogamma-(2-piperidyl) -propyl]-methyl 4quinazolones which comprises reacting a 3-[betaketo gamma (tetrahydro 2pyridyl) propyll methyl-d-quinazolone with not more than 1.4mol-equivalents of hydrogen in the presence of a hydrogenation catalystand in an inert solvent containing at least one moi-equivalent of anonoxidizing acid having a dissociation constant in water of at least 110 5. The method of preparing 3-[beta-ketogamma-(hydroxy-ZpiperidyDpropyl] methyl- 4-quinazolones which comprises reactin a 3-[beta keto gamma (hydroxy tetrahydro- 2 pyridyl) propyllmethyl--quinazolone with not more than 1.4 mol-equivalents of hydrogenin the presence of a hydrogenation catalyst and in an inert solventcontaining at least one molequivalent of a nonoxidizing acid having adissociation constant in water of at least 1X10- 6. The method ofpreparing 3-[beta-keto-= gamma-(hydroxy-2-piperidyl) -propy1l halo 4-quinazolones which comprises reacting aB-Ebetaketo gamma(hydroxy-tetrahydro 2 pyridyl)propyl]-halo-4-quinazolone with not morethan 1.4 mol-equivalents of hydrogen in the presence of a hydrogenationcatalyst and in an inert solvent containing at least one mol-equivalentof a nonoxidizing acid having a dissociation constant in water of atleast 1X10- 7. The method of claim 3 wherein said catalyst is platinumand said mineral acid is hydrochloric acid.

8. The method of claim wherein said catalyst is platinum and saidmineral acid is hydrochloric acid.

9. The method of claim 5 wherein said catalyst is platinum and saidmineral acid is hydrochloric acid.

10. The method of claim 6 wherein said catalyst is platinum and saidmineral acid is hydrochloric acid.

BERNARD R. BAKER. MERLE V. QUERRY.

No references cited.

1. THE METHOD OF PREPARING 3-(BETA-KETOGAMMA-(2-PIPERIDYL)-PROPYL) - 4-QUINAZOLONES AND ACID ADDITION SALTS THEREOF WHICH COMPRISES REACTING A3-(BETA-KETO-GAMMA-(TETRAHYDRO-2PYRIDYL)-PROPYL)-4-QUINAZOLONE WITH NORMORE THAN 1.4 MOL-EQUIVALENTS OF HYDROGEN IN THE PRESENCE OF AHYDROGENATION CATALYST AND IN AN INERT SOLVENT CONTAINING AT LEAST ONEMOL-EQUIVALENT OF A NONOXIDIZING ACID HAVING A DISSOCIATION CONSTANT INWATER OF AT LEAST 1X10-2.